Abstract:
UNLABELLED:Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant. SIGNIFICANCE:NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Stoeck A,Lejnine S,Truong A,Pan L,Wang H,Zang C,Yuan J,Ware C,MacLean J,Garrett-Engele PW,Kluk M,Laskey J,Haines BB,Moskaluk C,Zawel L,Fawell S,Gilliland G,Zhang T,Kremer BE,Knoechel B,Bernstein BE,Pear WS,Liudoi
10.1158/2159-8290.CD-13-0830subject
Has Abstractpub_date
2014-10-01 00:00:00pages
1154-67issue
10eissn
2159-8274issn
2159-8290pii
2159-8290.CD-13-0830journal_volume
4pub_type
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